Somatodendritic Kv2.1 channels are unique among voltage-gated ion channels in that, while having a broad and robust expression in neurons across mammalian brain, they play an exceptional conditional role in regulating neuronal excitability. Previous studies have shown that Kv2.1 in hippocampal pyramidal neurons appears to be relatively uninvolved in regulating neuronal excitability under conditions of low levels of neuronal activity, but becomes actively engaged under periods of high frequency firing, and in response to seizures and hypoxic/ischemic insults. This leads to homeostatic suppression of neuronal excitability that contributes to neuroprotection. The dramatic transformation in Kv2.1 is mediated through dynamic and reversible activity-dependent changes in Kv2.1 phosphorylation, which impacts the localization and gating of Kv2.1 channels in neurons. This proposal is aimed at determining the molecular mechanism underlying regulation of Kv2.1 localization by phosphorylation state, the respective contribution of phosphorylation-dependent changes in Kv2.1 localization versus voltage-dependent gating in the observed Kv2.1-mediated suppression of neuronal excitability under conditions of high levels of neuronal activity, the signaling pathway whereby suppression of neuronal activity leads to enhanced phosphorylation of Kv2.1, and the effects of genetic Kv2.1 knockdown/knockout in vivo on the sensitivity of animals to seizures and hypoxia, and their subsequent recovery. These studies will yield important insights into the physiological and pathological regulation of Kv2.1 channels, which are key regulators of neuronal excitability in mammalian neurons. Moreover, they will provide important new information on the interaction of Kv channel cytoplasmic domains with intracellular signaling pathways that is crucial to integrating membrane excitability with neuronal physiology under both physiological and pathophysiological conditions.